Compositions containing bis-chromonyl compounds for inhibiting antigen-antibody reactions

ABSTRACT

Pharmaceutical compositions comprising a pharmaceutical carrier and a bis-chromonyl compound of the formula AND THERAPEUTICALLY ACCEPTABLE SALTS, ESTERS AND AMIDES THEREOF, IN WHICH R1, R2, R3, R4, R5 and R6 are each selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, hydroxyloweralkyl, haloloweralkyl, hydroxyloweralkoxy, loweralkoxyloweralkoxy and carboxyloweralkoxy; and X is selected from the group consisting of saturated and unsaturated, straight and branched hydrocarbon chains which may be interrupted by a member selected from the group consisting of benzene rings, dioxanyl, oxygen atoms and carbonyl groups, and which may be substituted by a member selected from the group consisting of halogen atoms, hydroxy groups and lower alkoxy groups are active to inhibit antigenantibody reaction.

United States Patent Fitzmaurice et al.

[15] 3,686,412 45] Aug. 22, 1972 Road, both of Holmes Chapel, England[22] Filed: Oct. 2, 1970 [21] Appl. No.: 77,711

Foreign Application Priority Data Mar. 25, 1965 Great Britain ..12626/65Dec. 9, 1965 Great Britain ..524l4/ 65 Related US. Application [60]Continuation of Ser. No. 765,722, July 30, 1968, abandoned, which is adivision of Ser.

P [58] Fieldbisearchwf. ..'..'..'.'.j.. f24/i83 Primary Examiner-RichardL. Huff Attorney-Wenderoth, Lind & Ponack [5 7] ABSTRACT Pharmaceuticalcompositions comprising a pharmaceutical carrier and a bis-chromonylcompound of the formula O R II I l I l H020 C02H O O and therapeuticallyacceptable salts, esters and amides thereof, in which R, R R R, R arid Rare each selected from the group consisting of hydrogen, halogen,hydroxy, lower alkyl, lower alkoxy, hydroxyloweralkyl, haloloweralkyl,hydroxyloweralkoxy, loweralkoxyloweralkoxy and carboxyloweralkoxy; and Xis selected from the group consisting of saturated and unsaturated,straight and branched hydrocarbon chains which may be interrupted by amember selected from the group consisting of benzene rings, dioxanyl,oxygen atoms and carbonyl groups, and which may be substituted by amember selected from the group consisting of halogen atoms, hydroxygroups and lower alkoxy groups are active to inhibit antigenantibodyreaction.

10 Claims, No Drawings COMPOSITIONS CONTAINING BIS-CHROMONYL COMPOUNDSFOR INHIBITING ANTIGEN- ANTIBODY REACTIONS This application is acontinuation of application Ser. No. 765,722, filed July 30, 1968 (nowabandoned) which application is in turn a division of application Ser.No. 536,281, filed Mar. 22, 1966, now US. Pat. No. 3,419,578.

This invention is concerned with improvements in or relating to newchemical compounds and pharmaceutical compositions containing them.

It has now been found that certain new chromone derivatives, ashereinafter defined, possess special activity as inhibitors of theeffects of certain types of antigen-antibody reaction, as evidenced, forexample, by in vivo tests.

According to the invention, therefore, there are provided as newcompounds bis-chromonyl compounds of the formula:

o 1: it

11010 430m 0 R o R! R and functional derivatives thereof, in which R, RR, R", R and R are the same or different and each is a hydrogen orhalogen atom (e.g., a chlorine, bromine, iodine or fluorine atom), alower alkyl (e.g., a methyl, ethyl, propyl, isopropyl, butyl ortertiaryl butyl group), hydroxy, lower alkoxy (e. g. a methoxy, ethoxy,propoxy, isopropoxy, butoxy or tertiary butoxy group) or substitutedlower alkyl or lower alkoxy group, (for example a hydroxyloweralkoxy,loweralkoxyloweralkoxy, carboxyloweralkoxy, hydroxyloweralkyl orhaloloweralkyl such as chloro-, bromo-, iodoor fluoro-loweralkyl) and Xis a saturated or unsaturated, substituted or unsubstituted, straight orbranched polymethylene chain which may be interrupted by one or morecarbocyclic rings or oxygen containing heterocyclic rings, (e.g.benzene, dioxan, tetrahydrofuran, or dihydropyran rings), oxygen atomsor carbonyl groups.

In general, it is preferred that not more than one of R R and R and notmorethan one of R, R and R is other than hydrogen.

Accordingly a preferred embodiment of the invention is constituted bybis-chromonyl compounds of the formula:

OOH mo 0/ \O/ and functional derivatives thereof, in which R and R arethe same or are different and each is a hydrogen or halogen atom or analkyl, hydroxy, alkoxy or substituted alkoxy group, and X has themeaning defined above.

Particularly preferred compounds according to the invention are those inwhich all of R, R R, R, R and R are hydrogen and accordingly a furtherpreferred embodiment of the invention is constituted by bischromonylcompounds of the formula:

and functional derivatives thereof, in which X has the meaning definedabove.

The group X may be any of a wide variety of groups. Thus for example, itmay be a straight or branched saturated or unsaturated hydrocarbonchain. Further, X may be such a chain interrupted by one or more oxygenatoms, carbonyl groups or carbocyclic or heterocyclic rings and may besubstituted by one or more halogen atoms (e.g. chlorine, bromine, iodineand fluorine atoms), or hydroxy or lower alkoxy (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert.butoxy, etc.) groups. Specificexamples of the group X are groups of the formula:

:gn qgqnomooniononcm yc.

w-com and its functional derivatives.

Functional derivatives of the compounds according to the inventioninclude salts, esters and amides of one or more of the carboxylic acidfunctions present and esters of any hydroxylic functions present.

Salts of the bis-chromonyl compounds which may be mentioned are saltswith physiologically acceptable cations, for example, ammonium salts,metal salts such as 3 alkali metal salts (e.g. sodium, potassium andlithium salts) and alkaline earth metal salts (e.g. magnesium andcalcium salts) and salts with organic bases, e.g. amine salts such aspiperidine, triethanolarnine and diethylarninoethylamine salts.

Esters which may be mentioned include simple alkyl esters (e.g. methyl,ethyl, propyl, isopropyl, butyl and tertiary butyl esters) and amideswhich may be mentioned include simple amides (for example amides withammonia and lower alkylarnines such as methylamine, ethylamine etc) andmore complex amides with amino acids such as glycine.

The new bis-chromonyl compounds according to the invention have beenshown to inhibit the release and/or action of toxic products which arisefrom the combination of certain types of antibody and specific antigen,e.g. the combination of reaginic antibody with specific antigen. In man,it has been found that both subjective and objective changes whichresult from the inhalation of specific antigen by sensitized subjectsare markedly inhibited by prior administration of the new bischromonylcompounds. Thus the new compounds are of great value in the prophylactictreatment of extrinsic allergic asthma. It has also been found that thenew bis-chromonyl compounds are of value in the prophylactic treatmentof so-called intrinsic asthma (in which no sensitivity to extrinsicantigen can be demonstrated).

It has also been found that in certain virus/antibody neutralizationsystems the new bis-chromonyl compounds enhance the neutralizingcapacity of the antiserum, and thus the new compounds may find use inthe treatment of viral infections.

According to a further feature of the invention, therefore, there isprovided a pharmaceutical composition comprising a bis-chromonylcompound according to the invention, preferably in the form of a salt,in association with a pharmaceutical carrier or diluent. There is alsoprovided a process for the manufacture of a pharmaceutical compositionwhich comprises mixing a bis-chromonyl compound with a carrier ordiluent.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the desired route of administration, i.e.orally, parenterally or by inhalation.

The compositions according to the invention are especially useful forthe prophylactic treatment of asthma, i.e. the compositions areadministered to the patient at regular intervals (e.g. 4-6 hourly) inorder to inhibit the effects of asthmatic attacks from which the patientmay suffer. Then employed in this manner, the dosage of composition ispreferably such that from 1-50 mg. of active compound are administeredto the patient at each administration.

In general, for the prophylactic treatment of asthma, the compositionswill be in a form suitable for administration by inhalation. Thus thecompositions may comprise a suspension or solution of the activeingredient in water for administration by means of a conventionalnebulizer. Alternatively the compositions may comprise a suspension orsolution of the active ingredient in a conventional liquified propellantsuch as dichlorodifluoromethane or chlorotrifluorethane to beadministered from a pressurized container. The compositions may alsocomprise the solid activeingredient diluted with a solid diluent, e.g.lactose, for administration from a powder inhalation device.

The pharmaceutical compositions according to the invention generallycontain a minor proportion of bischromonyl compound and a majorproportion of carrier or diluent. Thus, for example, the solutions foradministration by a conventional nebulizer will comprise a dilutesolution, e.g., about 0.5 percent, in sterile water, and compositionscomprising suspensions or solutions in pressurized propellants willcontain, for example, about 2 percent of the active bis-chromonylcompound. However, where the composition comprises the solidbis-chromonyl compound diluted with a solid diluent, the diluent may bepresent in less, equal or greater amount than the solid activeingredient, for example the diluent may be present in an amount of from50 to percent by weight of the solid active ingredient.

The invention also includes within its scope a method of inhibiting theeffects of the antigen-antibody reaction which comprises the priorapplication to the area of the antigen-antibody mechanism atherapeutically effective amount of a bischromonyl compound according tothe invention.

According to a particular embodiment, the invention is for a method ofrelieving or preventing allergic airway obstruction which comprisesadministering to the patient a therapeutically eflective amount (e.g.l-50 mg) at suitable intervals, of a bis-chromonyl compound according tothe invention, particularly in the form of a salt.

The raw compounds according to the invention are prepared by linkingtogether two chromone-2-carboxylic acids or precursors therefor.

According to a further feature of the invention, therefore, there isprovided a process for the preparation of bis-chromonyl-compounds of theformula:

and functional derivatives thereof, in which R, R R, R, R and R have themeanings defined above, which comprises reacting in one or more stages,

(a) a compound of the formula:

(b) a compound of the formula:

and 7 c. a compound of the formula:

AX'S

in which Z is a hydroxy group and Y is a hydrogen atom, a group COCH ora group COOH (in which R is an alkyl group), or Y and Z together form achain (in which W is a carboxylic acid group or a functional derivativethereof or a group convertible to a carboxylic acid group or afunctional derivative thereof), Y and Z have the same definition as Yand Z above and may be the same or difierent; and A and B are the sameor different and each is a group capable of reacting with a hydroxylgroup to form an ether linkage, or one of A and B is a group capable ofbeing converted to such a reactive group; and X is such that the group AX'B' (in which A and B are the residues of A and B after the formationof other linkages) has the same meaning as X; to form a compound of theformula:

and, if necessary, intermediately or subsequently converting Y and Zand/or Y and Z to chains of the formula CO-CH C(COOH)--O, or functionalderivatives thereof.

As stated above, the process according to the invention may be carriedout in one or more stages. Thus, it may be carried out in two stages asfollows:

This procedure will generally be adopted when the two chromone moietiesof the desired bis-chromonyl compound are different, ie when R, R and Rare different from R, R and R. In the two stage process, the groupings Yand Z or Y and Z may be modified at an intermediate stage but, ingeneral, it is not preferred to follow this route. When the two chromonemoieties of the desired bis-chromonyl compound are the same the reactionmay be carried out in two stages, or preferably, if Y and Z have thesame meanings as Y and Z, in one stage, i.e. by reaction of a compoundof the formula:

with a compound of the formula:

When the reaction is carried out in two stages the compound A-XB may besuch that one of A and B is a group capable of being converted to anether linkage forming group. When both A and B are ether linkage forminggroups, the first stage of a two stage reaction will, of course, becarried out using substantially equimolecular proportions of the twocompounds.

Examples of groups A and B capable of reacting with a phenolic hydroxylgroup, such that an ether linkage is formed by X and the hydroxyl group,include halogen atoms, e.g. chlorine, bromine or iodine atoms, or otheranion forming groups such as tosylate or methane sulphonate groups.Where the group A contains a hydroxy group beta to the subsequentlyformed ether linkage the group A or B may represent an epoxide group,giving rise to a residue A or B of CH,-- CHOH. The groups A and B may bethe same or different; thus a compound AX'-B capable of yielding aZ-hydroxy-trimethylene linkage is the compound:

Groups capable of being converted to reactive groups such that an etherlinkage may be subsequently formed include hydroxyl groups which may beconverted to halogen substituents or other anion forming groups such astosylate or methane sulphonate. The group A or B may alternatively be avinyl group (CH CH which may subsequently be converted to an epoxide orhalohydrin group. Thus, an example of a compound A--XB which may be usedto produce a 2- hydroxy-tn'methylene linkage is allyl bromide.

The reaction between the chromone moiety or precursor therefor and thelinking compound A-X' S will be carried out under the conditionsnormally employed for the formation of ether linkages. Thus, thereaction will generally be carried out in the presence of aqueous alkalior a solvent such as acetone or dioxan and at elevated temperature.There the ether linkage formation is carried out by reaction of thearomatic hydroxy group and a compound A-XB in which A and/or B is ananion forming group (e.g. halogen, methanesulphonate etc) the reactionis desirably carried out in the presence of an acid binding agent suchas an alkali metal carbonate (e.g. sodium carbonate or potassiumcarbonate) or an organic acid binding agent such as pyridine,diethylaniline or triethylamine. Where A and/or B is an epoxide group ofether forming reaction may be conveniently carried out in the presenceof a suitable catalyst, e. g. in the presence of a quaternary ammoniumhydroxide.

5 The conversion, if necessary, of Y and Z and/or Y and Z to the desiredchain CO-CH C(COOH)- O or functional derivative thereof will be carriedout simultaneously if Y and Z are the same as Y and Z and in separatestages if Y and Z are not the same as Y' and Z. It is, however,generally preferred that Y and Z are the same as Y and Z since thisreduces the number of chemical stages involved.

In the following description of methods of converting Y and Z to thedesired chain CO-CH C(COOH) O- or functional derivatives thereofreference will compound in which Y is a group COCH and Z is a hydroxygroup (i.e. a substituted o-hydroxyacetophenone) to a chain -C0-CHC(COOR) 7 (in which R is a hydrogen atom or an alkyl group); i.e.

in which R is a halogen atom or a group OR'(in which R is an alkylgroup), R and R are both halogen atoms and R is'a group OR or R and Rtogether pr ent autum m an R" is #L halogen atom or a group OR.

Thus a particularly preferred process involves reaction of theortho-hydroxy-acetophenone with a dialkyl oxalate, such as diethyloxalate, preferably in the presence of a condensation agent such as analkali metal alkoxide, e.g. sodium ethoxide, sodamide, metallic sodiumor sodium hydride and conveniently in the presence of an organic solventsuch as ether, dioxan, ethanol or benzene. This process goes through anintermediate of the formula:

where R is the alkyl group of the dialkyl oxalate, which intermediatemay be cyclized directly by heating or may be isolated and cyclized byheating in a suitable solventin the presence of a cyclization agent suchas an acid.

When the oxalic acid derivative is of the formula:

R'O-C(Hal),-COO

in which R" is an alkyl group, e.g. ethyl ethoxwhich may then beoxidatively cyclized to the desired chromone-Z-carboxylic acid.Non-oxidative cyclization gives rise to the corresponding chromanonewhich may be converted to the chromone as described below.

A different route for the formation of the desired chromonyl compoundinvolves the conversion of Y and Z (when Y is -COCH and Z is OI-l) to anintermediate of the formula:

or functional derivative thereof, and subsequent 'conversion of thegroup V to a carboxylic acid group or functional derivative thereof.

Examples of the group V are the nitrile group which may be hydrolyzed toa carboxylic acid group and groups such as methyl, hydroxymethyl,halomethyl (e.g. chloromethyl, bromomethyl, dichloromethyl,trichloromethyl), formyl, acetyl, vinyl and styryl groups, oxidizable orhydrolyzable to a carboxylic acid group.

The 2-methyl chromone may be prepared from the o-hydroxyacetophenone bycondensation with an alkyl acetate, in a similar manner to thecondensation described above for the diallyl oxalate.

The 2-methyl chromone also serves as an intermediate in the preparationof a number of other oxidizable derivatives. Thus, the 2methyl chromonemay be converted into the corresponding 2-halomethylchromone, e.g., byreaction with hydrogen chloride and manganese dioxide in boiling aceticacid to produce a 2-chloromethyl chromone 'or'by reaction bromine inacetic acid to yield the 2-bromomethylchromone. The

ydichloroacetate, the reactants are desirably employed so insubstantially equimolecular proportions and the reaction is convenientlycarried 'out in the presence of a metallic catalyst such as finelydivided metallic platinum, palladium or ruthenium. When the oxalic acidderivative is of the formula:

Hal-CO-COOR e.g. ethyl oxalyl chloride, the reaction is convenientlycarried out in the presence of an acid binding agent. When the oxalatederivative is an oxalyl halide such as oxalyl chloride, the reaction issuitably carried out in the presence of an organic solvent and in thepresence of an acid binding agent.

The o-hydroxy-acetophenone may also be condensed with an ester ofglyoxalic acid to give a compound of the formula:

2-halomethyl chromone may be oxidized to the correspondingchromone-2-carboxylic acid, for example,

' with potassium permanganate, or may be hydrolyzed,

- ing, for example, chromium trioxide as reagent.

Condensation of the- 2-methyl-chromone with a benzaldehyde in thepresence of a condensation catalyst gives the 2-styryl chromone whichmay be oxidized to the corresponding chromone-2-carboxylic acid, forexample using potassium permanganate.

A number of the chromone derivatives, other than the 2-methyl chromone,convertible to the chromone- 2-carboxylic acid may be prepared directlyfrom the ohydroxy-acetophenone.

Thus, the 2-formyl chromone may be prepared by condensation of adialkoxy acetate of the formula:

(R'Oh'CH-COOR" Thus, the 2-forrnyl chromone may be reacted with'hydroxylamine to yield the '2-oxisino-chromone which may then bedehydrated to the 2-cyanochromone which may then be hydrolyzed to thechromone2-carboxylic acid or amide thereof under acid conditions.

The 2-styryl chromone may be prepared from the ohydroxyacetophenone byreaction with sodium cinna- 'mate and cinnanic anhydride (i.e. by theKostanecki reaction) or by reaction with a cinnamoyl halide, e.g.cinnamoyl chloride, in the presence of an acid binding agent to yieldthe cinnamate ester of the o-hydroxyacetophenone followed by treatmentwith a base, e.g. potassium carbonate, in the presence of an inertsolvent such as toluene or benzene to given an alphadiketone of theformula:

which is subsequently cyclized either by direct heating or by heating inthe presence of a cyclization agent (Baker Venkataraman reaction).

The 2-vinyl chromone may likewise be prepared' from theo-hydroxy-acetophenone by reaction with ethyl acrylate.

The compound in which Y is a hydrogen atom and Z is a hydroxyl group,i.e. the phenol of the formula:

may be converted to the corresponding chromone-2- carboxylic acid by anumber of methods.

For example, the chromone-2-carboxylic acid may be prepared by reactionof acetylene dicarboxylic acid or a dialkyl ester thereof, e.g. diethylacetylene dicarboxylate, with the phenol or with an alkali metal phenatethereof.

Where the acetylene dicarboxylic acid or ester thereof is reacted withthe alkali metal phenate, i.e. the compound of the formula:

in which M is an alkali metal atom, the reaction is desirably carriedout in the presence of an inert organic solvent or diluent to yield afumarate of the formula:

which is then, if necessary after hydrolysis, cyclized to the desiredchromone-2-carboxylic acid, for example by heating in the presence of acyclization catalyst such as sulphuric acid. In a modification of thisprocess the acetylene dicarboxylic said or ester thereof is replaced bya halo-furnaric acid or an ester thereof, e.g. diethyl chlorofumarate,or by a dihalosuccin ic acid or ester thereof.

20, The chromone-Z-carbdxylic acid may also be prepared from the phenolby reaction with a compound such as ethyl ethoxalylacetate.

In another method the phenol may be esterified, e.g.

l with ethyl ethoxalyl chloride to give an ester of the formula:

O2C.CO2Et which may subsequently be cyclized in the presence of aceticacid or a derivative thereof (e.g. ethyl acetate or acetyl chloride) togive the desired chromone-Z-carboxylic acid.

The phenol may alternatively be condensed with maleic anhydride to givea compound of the formula:

which may then be oxidatively cyclized to the desiredchromone-Z-carboxylic acid. Non-oxidative cyclization gives rise to thecorresponding chromanone which may then be converted to the chromone asdescribed below.

The compound in which Z is a hydroxyl group and Y is a group COOR i.e.the substituted salicylic acid ester of the formula:

may be converted to the desired chromone-Z-carboxylic by reaction with apyruvate ester of the formula:

CH --CO-COOR' if desired in the presence of a condensation agent such asan alkali'metal alkoxide (e.g. sodium ethoxide), sodarnide, metallicsodium or sodium hydride, and

preferably in the presence of an organic solvent such as ethanol ordioxan.

When Y and Z together form a chain w -o -CH=(|]0 in which W is thedesired carboxylic acid group or functional derivative thereof,obviously no modification of Y and Z will be necessary. When W is groupconvertible to a carboxylic acid group, or a functional derivativethereof, it will have the same meaning as defined for V above and may beconverted to the corresponding carboxylic acid group as described for Vabove.

When Y and Z together form a chain i.e. a chromanone, the group W willremain unchanged or be converted to a carboxylic acid group as necessaryand further the chromanone will need to be dehydrogenated to thecorresponding chromone; which dehydrogenation may be carried out eitherbefore or after any conversion of W.

The dehydrogenation of the chromanone of the formula:

may, for example, be effected using solenium dioxide or other suitabledehydrogenating agents such as palladium black or chloranil.

Alternatively, dehydrogenation may be carried out by brominationfollowed by dehydrobromination. Thus, the chromanone may be brominatedusing N- bromosuccinimide in an inert solvent or by treatment withpyridinium perbromide in an inert solvent such as chloroform in thepresence'of a free radical catalyst such as benzoyl peroxide, to yieldthe 3-bromo derivative which may be subsequently dehydrobrorninated.

The processes described above generally lead to the formation of thechromone-2-carboxylic acids as such or in the form of their esters.These may be readily converted to other functional derivatives, e.g.salts or amides, by conventional methods.

The majority of the intermediates produced by the linking of the twochromone moieties or precursors therefor are in themselves new.

According to the invention, therefore, there are provided as newcompounds, compounds of the formula:

in which R, R R", R, R R, X, Y, Z, Y and Z have the meanings definedabove, provided that not more than one of Y and Z and Y and 2'represents a chain CO-CH C(COOH)O or a functional derivative thereof andfurther provided that when R, R R

R, R and R are hydrogen and Y and Y' are groups COCl-l and Z and Z arehydroxyl groups, X is not a group -CH CHOHCH linking the two positionspara to the groups Y and Y.

This invention also provides a process for the preparation of the newintermediates which comprises reacting in one or more stages:

(a) a compound of the formula:

(b) a compound of the formula:

and

c. a compound of the formula:

A-X-B in which A and B have the meanings defined above.

In order that the invention may be well understood, the followingexamples are given by way of illustration only.

EXAMPLE 1 a. l,3-Bis( 2-acetyl-3-hydroxyphenoxy)propane A mixture of30.4 parts 2,6-dihydroxyacetophenone, 20.2 parts of 1,3-dibromopropaneand 12.8 parts powdered potassium carbonate were heated under reflux in200 parts by volume of acetone for 72 hours. THe acetone solution wasfiltered and the solid residue was washed first with acetone and thenwith water. The combined acetone filtrate and washings were evaporatedleaving an oil which, on being boiled with ether, gave pale yellowcrystals. These were combined with the first obtained solid andextracted with refluxing isopropanol in a Soxhlet extractor for severaldays to obtain 16.1 parts of l,3-bis(2-acetyl-3-hydroxyphenoxy)propaneas almost colorless crystals melting between 184 and 185C.

Analysis:

Found: C, 65.4; H, 5.68%

C I- O requires: C, 66.2; H, 5.81%

b. Diethyl ester of l,3-bis(2-carboxychromon-5-ylox- Y)P 'P A solutionof 6.9 parts l,3-bis(2-acetyl-3-hydroxyphenoxy) propane in 15 parts byvolume of diethyl oxalate was added to a solution of 3 parts sodium in30 parts by volume of ethanol and 50 parts by volume of benzene and themixture was heated gently under reflux for 20 hours. It was then pouredinto a large volume of ether and the precipitated solid was filtered,washed with ether and dried. It was then dissolved in water andacidified to obtain a sticky solid. This was boiled with about 50 partsof ethanol containing a catalytic amount of hydrochloric acid for about10 minutes, when crystals began to form. The solution was cooled andfiltered to obtain 7.4 parts of solid melting between 178 and 180C. Thiswas recrystallized from 200 parts by volume of a 1:2 mixture of benzeneand ethanol to nnlnln In on obtain a first crop of 4.5 partsof thediethyl ester of 1.3-bis(2-carboxychromon-5-yloxy)propane, meltingbetween 182 and 183C.

Analysis:

Found: C, 63.2; H, 4.60%

C H O requires: C, 63.7; H, 4.72%

c. salt of 1,3-bis(2-carboxychromon-5-yloxy)propane A suspension of 3parts of the diethyl ester of 1,3-

bis(2-carboxychromon-5-yloxy)propane-in 50 parts by volume of boilingethanol was treated with 11.6 parts by volume of 1.015N aqueous sodiumhydroxide. Water was added until-clear solution was obtained. This wastreated with charcoal, filtered and concentrated by boiling, with theoccasional addition of more ethanol. On cooling 2.2 parts of colorlesscrystals of the disodium salt of 1,3-bis( 2-carboxychromon-5-ylox--y)propane monohydrate were obtained.

Analysis: I

Found: C, 54.1;H., 2. 86%

cggHmNagomHgo requires: C, 53.7; H., 3.11%

EXAMPLE 2 2,500 parts of hot isopropanol was added, with stirring,

under reflux, a solution of 233 parts of 85% KOH in 2,500 parts ofisopropanol and sufl'lcient water (ca. 100

parts) to dissolve the solid. The mixture was heated,.

' stirring, under reflux for 48 hours. Half the solvent was thendistilled off and 5,000 parts of water were added. The mixture wascooled and the solid filtered off and washed with isopropanol and ether.It was then recrystallized from 12,500 parts of isopropanol to obtain afirst crop of 380 parts and a second crop, after concentration, of 300parts of 1,3-bis(2-acetyl-3- hydroxyphenoxy)-2-hydroxypropane identicalwith that obtained in Example 2 (a) above. 0. Diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)- Z-hydroxypropane By the method of Example lb4.6 parts of 1,3-bis(2- acetyl-3-hydroxyphenoxy)-2-hydroxypropane werereacted with diethyl oxalate and the product cyclized to obtain 4.4parts of pure diethyl ester of1,3-bis(24:arboxychromon-S-yloxy)-2-hydroxypropane as pale yellowcrystals melting between 1 80 and 182 from a mixture of benzene andpetrol. Analysis: Found: C, 61.5; H, 4.61% C H O requires: C, 61.8; H,4.57% d. Disodium salt of1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane By the method ofExample 10, 4 parts of the diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane were saponified to obtain 3.2parts of the disodium salt tetrahydrate as colorless crystals fromaqueous alcohol. Analysis: Found: C, 47.8; H, 3.8; Na, 7.7% C H Na O 4HO requires: C, 47.3; H, 3.79; Na, 7.7% e.1,3-Bis(2-carboxychromon-5-y1oxy)-2-hydroxypropane A solution of thedisodium salt of 1,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane inwater was acidified and the precipitate was recrystallized from ethanolplus ether to obtain l,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropanemonohydrate as colorless crystals melting with decomposition between 216and 217. Analysis: Found: C, 56.7; H, 3.44% CzaHmOnHgO requires: C, H,Dehydration of the monohydrate in vacuo at C gave the anhydrous acidmelting between 241 and 242C with decomposition. f. Calcium salt of1,3-bis(2-carboxychromon5-yloxy)- 2-hydroxypropane The disodium salt of1,3-bis(2-carboxychromon-5- yloxy)-2hydroxypropane (0.8 parts) dissolvedin the minimum volume of warm water was treated with a solution of 0.225parts of calcium nitrate in a small volume of water, to obtain thesparingly soluble calcium salt. The mixture was cooled and filtered, andthe solid was washed with cold water and dried at 1 10C. Analysis:Found: Ca, 7.19% C H, CaO 3H O requires: Ca, 7.14% g. Magnesium salt of1,3-bis(2-carboxychromon-5- yloxy)-2-hydroxypropane A suspension of 2parts of 1,3-bis( 2-carboxychromon-S-yloxy)-2-hydroxypropane in 20 partsof water was treated with 0.36 parts of magnesium carbonate. The mixturewas boiled with stirring until homogeneous, cooled, filtered and driedat 110C to obtain 2.3 parts of the magnesium salt. h. Dipiperidine saltof 1,3-bis( 2-carboxychromon-5- yloxy)-2-hydroxypropane A suspension of2 parts of l,3-bis(2-carboxychromon-S-yloxy )-2-hydroxypropane in 20parts of water was treated with 0.7 part of piperidine. The mixture waswarmed under reflux until a clear solution was obtained after which itwas cooled and dehydrated by freeze-drying to obtain 2.8 parts of thedipiperidine salt of 1 ,3-bis(2-carboxychromon-5-y1oxy)-2-hydroxypropane. Analysis: Found: C, 39.0; H, 6.12; N, 4.00% CH NO,,.2H O requires: C, 59.1; H, 5.67; N, 4.18%

EXAMPLE 3 a. 1.4-Bis(2-acetyl-3-hydroxyphenoxy)but-Z-ene By the methodof Example 1a, 15.2 parts of 2,6- dihydroxyacetophenone were condensedwith 10.7 parts of 1,4-dibrembut-2-ene to obtain 6 parts of 1,4-bis(2-acetyl-3-hydroxyphenoxy)but-2-ene melting between and 146 fromacetone. b. l,4-Bis(2-carboxychromon-5-y1oxy )but-2-ene By the method ofExample 1b, 5 parts of l,4-bis(2- acetyl-3-hydroxyphenoxy)but-2-ene werecondensed with diethyl oxalate to obtain 3 parts of the diethyl ester of1,4-bis(2-carboxychromon-5-yloxy)but-2-ene as yellow crystals meltingbetween 215 and 217C from ethanol.

Analysis:

Found: C, 64.1; H, 4.69%

C H O requires: C, 64.6; H, 4.6%

Saponification of 2 parts of the diethyl ester of 1,4-bis(2-carboxychromon-5-yloxy)but-2-ene by the method of Example 1 (a)gave 1.5 parts of the disodium salt.

Acidification of an aqueous solution of this sodium salt gave the freeacid monohydrate, melting between 193 and 195.

Analysis: Found: C, 59.6; H, 3.56% C H O H O requires: C, 59.7; H, 3.73%

EXAMPLE 4 1 12-bis( 2-carboxychromon-5-yloxy )-2,1 1-dihydroxy-4,9-dioxadodecane A solution of parts 2,-dihydroxyacetophenone, 5.6parts butane-1,4-diol diglycidyl ether and 0.1 part of 40 percentaqueous solution of benzyltrimethylammonium hydroxide in 14 parts dioxanwas heated at 100C in a sealed vessel for 60 hours. The dioxan wasremoved under reduced pressure leaving a thick yellow oil. This wasextracted several times with boiling ether and the combined extractswere fractionally precipitated with petrol. The first fraction, whichwas about 5 parts of a clear yellow oil, could not be crystallized ordistilled but had an infra-red spectrum consistent with that expectedfor l,12-bis(2-acetyl-3- hydroxyphenoxy)-2,1l-dihydroxy-4,9-dioxadodecane. This was condensed with diethyl oxalateby the method of Example lb to obtain 3 parts of the diethyl ester of 1I 2-bis( 2-carboxychromon-5-yloxy)-2,l l-dihydroxy- 4,9-dioxadodecane asan oil. This oil was stirred and warmed with a saturated aqueoussolution of sodium bicarbonate until dissolved. The solution wasfiltered and acidified with dilute hydrochloric acid. The precipitatewas dissolved in ethanol plus ethyl acetate, treated with charcoal,filtered and precipitated with petrol and the solid was recrystallizedfrom acetone plus ether to obtain 1 part of pure 1,12-bis(2-carboxychromon-5-yl0Xy )-2, 1 1-dihydroxy-4,9-dioxadodecane dihydrate ascolorless crystals melting with decomposition at 80C. Analysis: Found:C, 55.3; H, 5.24% C H O 2H O requires: C, 55.3; H, 5.22%

l ,1 2 Bis( 2-carboxychromon-5-yloxy)-2,1 l-

dihydroxy-4,9-dioxadodecane dihydrate (0.325 parts),

was dissolved in a solution of 0.084 parts sodium bicarbonate in 100parts water. The solution was filtered and freeze-dried to obtain 0.3parts of the disodium salt tetrahydrate. Analysis: Found: C, 48.7; H,4.75%

- C H Na O 4H O requires: C, 49.3; H, 4.9%

EXAMPLE 5 a. 1,4-Bis(2-acetyl-3-hydroxyphenoxy)butane By the method ofExample la 2,6-dihydroxyacetophenone was reacted with 1,4-dibromobutaneto obtain l,4-bis(2-acetyl-3-hydroxphenoxy)butane melting between 219and 221C from benzene. Analysis: Found: C, 66.0; H, 6.0%

C H O requires: C, 67.0; H, 6.2% b. Diethyl ester of1,4-bis(2-carboxychr0mon-5-yloxy)butane By the method of Example lb1,4-bis(2-acetyl-3- hydroxyphenoxy)butane was condensed with diethyloxalate to form the diethyl ester of1,4-bis(2-carboxychromon-5-yloxy)butane melting between 195 and 199Cfrom a mixture of ethyl acetate and isopropanol. Analysis: Found: C,62.4; H, 5.1% c n q n o requires: C, 62.3; H, 5.2% c. l,4-Bis(2-carboxychromon-5-yloxy)butane The diethyl ester of1,4-bis(2-carboxychromon-5- yloxy)butane was hydrolyzed by heating withaqueous sodium bicarbonate until dissolved, filtering and acidifying thesolution. The precipitate was recrystallized from methanol to obtainpure l,4-bis(2-carboxychromon-5-yloxy)butane monohydrate melting between228 and 230C. Analysis: Found: C, 58.6; H, 3.03%

C H O H O requires: C, H,

EXAMPLE 6 1 ,5-Bis( 2-earboxychromon 5-yloxy )pentane2,6-Dihydroxyacetophenone was reacted with 1,5-

dibromopentane as in Example 10 to obtain 1,5-bis( 2-acetyl-3-hydroxyphenoxy) pentane' melting between 131 and 133C frombenzene.

Analysis:

Found: C, 67.4; H, 6.3%

C H O requires: C, 67.7; H, 6.5%

This diketone was condensed with diethyl oxalate as in Example 1b toobtain the diethyl ester of l,3-bis( 2- carboxychromon-S-yloxy)pentane,melting between and 152C from ethanol.

Analysis: Found: C, 64.6; H, 5.3% C d-I 0 requires: C, 64.8; H, 5.3%

The ester was hydrolyzed as in Example 5(c) to obtain the acid as amonohydrate melting between 226 and 228C from ethanol.

Analysis: Found: C, 60.3; H, 4.7% C H O H O requires: C, 60.2; H, 4.4%

The acid was subsequently converted to the disodium salt by the methodof Example 50.

EXAMPLE 7 1 ,6-Bis( 2-carboxychromon-5 -yloxy )hexane2,6Dihydroxyacetophenone was reacted with 1,6-

dibromohexane as in Example 1a to obtain 1,6-bis(2- The ester washydrolyzed as in Example 50 to obtain 1 EXAMPLE 8 l 10-Bis(2-carboxychromon-5 -yloxy)deca.ne

2,6-Dihydroxyacetophenone was condensed with l,l-dibromodecane as inExample 1a to obtain 1,10-

bis(2-acetyl-3-hydroxyphenoxy) decane between 102.5 and 104C from ethylacetate.

Analysis:

Found: C, 70.0; H, 7.4%

C l-1 0 requires: C, 70.6; H, 7.7%

This diketone was reacted with diethyl oxalate as in Example lb toobtain the diethyl ester of l,10-bis(2- carboxychromon-S-yloxy)decanemelting between l46.5 and 148C from ethanol plus dioxan.

Analysis: Found: C, 67.4; H, 6.45% C H O requires: C, 67.3; H, 6.3%

The ester was hydrolyzed by boiling with aqueous sodium bicarbonate toobtain the sparingly soluble disodium salt which was recrystallized fromwater. Analysis:

Found: C, 61.0; H, 5.2% c n Na o requires: C, 60.6; H, 4.7%

EXAMPLE 9 l ,7-Bis( 2-carboxychromon-5-yloxy )-2,6-dihydroxy-4-oxaheptane 2,6-Dihydroxyacetophenone was reacted with diglycidyl etheras in Example 4 to obtain 1,7-bis(2- acetyl-3-hydroxyphenoxy)2,6-dihydroxy-4-oxaheptane melting between 129 and 131C from ethylacetate plus petrol.

Analysis: Found: C, 60.4; H, 6.3% C H O requires: C, 60.8; H, 6.0%

This diketone was reacted with diethyl oxalate to obtain the bichromonediethyl ester as an oil which could not be crystallized, This ester washydrolyzed as in Example 50 to obtain1,7-bis(2-carboxychromon-5-yloxy)-2,6-dihydroxy-4-oxaheptane monohydratemelting between 216 and 218C.

Analysis: Found: C, 55.6; H, 3.4% c n o u o requires: C, 55.7; H, 4.3%

The disodium salt was subsequently prepared as in Example 50.

EXAMPLE l0 1,5-Bis( 2-carboxychromon-5-yloxy )-3-oxapenta.ne

2,6-Dihydroxyacetophenone was condensed with 2,2'-dibromodiethyl ether,as in Example 1a to obtain 18 Analysis: Found: C, 62.3; H, 4.9% C H Orequires: C, 62.4; H, 4.9%

The ester was hydrolyzed as in Example 50 to obtain the acid meltingbetween 219 and 220C from ethanol plus dioxan.

Analysis: Found: C, 59.8; H, 3.9% C H O requires: C, 59.8; H, 3.8%

The disodium salt of the acid was subsequently prepared as in Example50.

EXAMPLE ll 1 ,4-Bis( 2-carboxychromon-5-yloxy )-2,3-dihydroxybutane2,6-Dihydroxyacetophenone was reacted with 1,223,4-bisepoxybutane as inExample 4 to obtain 1,4-bis(2-acetyl-3-hydroxyphenoxy)-2,3-dihydroxybutane, melting between 21 1and 212C from dioxan. Analysis:

Found: C, 61.0; H, 5.7% C H O requires: C, 61.5; H, 5.7%

This was condensed with diethyl oxalate as in Example lb to obtain thediethyl ester of l,4-bis(2-ca.rboxychromon-S-yloxy)-2,3-dihydroxybutanemelting between 224 and 226C.

Analysis: Found: C, 59.2; H, 4.6% c r-[ o requires: C, 60.6; H, 4.7%

This was hydrolyzed by the method of Example 5c to obtain the acid as adihydrate melting between 260 and 262C.

Analysis: Found: C, 54.0; H, 3.7%

C H O ZH O requires: C, 54.0; H, 4.1%

5 acetyl-3-hydroxyphenoxy)-2-hydroxybutane This was subsequentlyconverted to the disodium salt as in Example 5 c.

EXAMPLE l2 1 ,4-Bis( 2-carboxychromon-5-yloxy)-2-hydroxybutane2,6-Dihydroxyacetophenone was condensed with 1- bromo-3,4-epoxybutane byboiling in acetone in presence of potassium carbonate to obtainl,4-bis(2- melting between 207.5 and 208.5C from methanol.

Analysis: Found: C, 63.41; H, 5.8% C H O, requires: C, 64.2; H, 5.9%

This was condensed with diethyl oxalate as in Example lb to obtain thediethyl ester of l,4-bis(2-carboxychromon-S-yloxy)-2-hydroxybutanemelting between 216 and 217C from a mixture of chloroform, ethyl acetateand petrol.

Analysis: Found: C, 62.7; H, 5.2% C H O requires: C, 62.4; H, 4.9%

This was hydrolyzed as in Example 50 to obtain the acid as a monohydratemelting between 226 and 227C. Analysis: Found: C, 57.1; H, 3.9% C H O{H,O requires: C, 57.6; H, 4.0%

This was subsequently converted to the disodium salt as in Example 5c.

EXAMPLE 13 1 ,5-Bis( 2-carboxychromon-7-yloxy)pentane Ethyl7-hydroxychromone-2-carboxylate was condensed with one half equivalentof 1,5dibromopentane by heating in acetone in presence of potassiumcarbonate to obtain the diethyl ester of1,5-bis(2-carboxychromon-7-yloxy)pentane melting between 148 and 150Cfrom ethanol. Analysis: Found: C, 64.6; H, 5.3% C ,,H O requires: C,64.8; H, 5.3%

This ester was hydrolyzed as in Example 50 to obtain the said meltingbetween 283 and 284C. Analysis: Found: C, 61.8; H, 4.2% C H O requires:C, 62.4; H, 4.2%

The acid was subsequently converted to the disodium salt by the methodof Example 50.

EXAWLE 14 1 10-Bis( 2-carboxychromon-5 -yloxy)-3,8-dioxa-4,7-dioxodecane Ethyl 2-hydroxyethoxy)chromone-2-carboxylate (1.4 parts) and0.4 parts succinyl chloride were dissolved in chloroform and treatedwith 0.5 parts pyridine. The mixture was heated under reflux for 16hours. The chloroform solution was washed with dilute hydrochloric acid,sodium carbonate solution and water and dried over sodium sulphate. Thechloroform was distilled to leave an oil which was solidified bytrituration with petrol. It was recrystallized from ethanol to obtain0.2 parts'of the diethyl ester of 1,10-bis(2-carboxychromon-5-yloxy)-3,8-dioxa-4,7-dioxodecane melting between144 and 146C.

Analysis: Found: C, 60.5; H, 4.97% C H O requires: C, 60.2; H, 4.69%

EXAMPLE 15 1 ,5-Bis( 2-carboxy-8-chlorochromon-5-yloxy )pentane Amixture of 4.62 parts of 1,5-bis( 2-acetyl-3-hydroxyphenoxy)pentane(from Example 6) and 2.7 parts of sulphuryl chloride in 300 parts of dryether was stirred for 7 hours at room temperature. The solution wasfiltered and evaporated to dryness leaving a yellow solid. This wasrecrystallized from ether to obtain 2.36 parts of1,5-bis(2-acetyl-4-chloro-3-hydroxyphenoxy)pentane as pale yellow prismsmelting at 96C.

This was condensed with diethyl oxalate as in Example 1b to obtain thediethyl ester of 1,5-bis( 2-carboxy-8 -chlorochromon-5-yloxy)pentanemelting between 162 and 164C from ethanol.

Analysis: Found: C, 57.7; H, 4.3% CzgHzeClzOo requires: C, 57.5; H, 4.3%

The ester was hydrolyzed as in Example 50 to obtain the acid, melting at244C from ethanol.

Analysis: Found: C, 54.2; H, 4.6; Cl, 12.9% C H Cl O requires; C, 54.7;H, 3.28; Cl, 12.9%

The acid was converted to the disodium salt by the method of Example 5c.

EXAMPLE 16 a. 2-( 2,3-Epoxypropoxy )-6-hydroxyacetephenone To a mixtureof 5.68 parts of 2,6-dihydroxyacetophenone, 10.3 parts ofepichlorohydrin and 3 parts (by volume) of ethanol which was stirred andgently refluxed, was added slowly a solution of 2.58 parts of potassiumhydroxide in 7 parts (by volume) of ethanol and 1 part (by volume) ofwater. The mixture was then stirredand refluxed for 1 hour, then aftercooling an excess of water was added and the product was extracted intoether and the solution was dried over sodium sulphate. After removingthe drying agent and the solvent 5 parts of a crude oil remained. Thisoil was extracted using hot petrol ether (b.p. 4060) and on coolingyellow crystals of 2-(2,3-epoxypropoxy)-6- hydroxyacetophenone m.p.61-63 separated. Analysis:

Found: C, 63.5; H, 5.7%

C H Q, requires: C, 63.45; H. 5.8%

b. 1-(2-Acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2hydroxypropane.

A mixture of 5 parts of 2-(2,3-epoxypropoxy)-6- hydroxyacetophenone, 3.8parts of resacetophenone, 20 parts (by volume) of dioxan and 5 drops oftrimethyl benzyl ammonium hydroxide solution were heated at C in asealed bottle overnight. After cooling the product crystallized out andwas recrystallized from dioxan to yield 2 parts of 1-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl3-hydroxyphenoxy-2-hydroxypropanemelting between 182 and C.

Analysis: Found: C, 62.8; H, 5.4% C I-1, 0 requires: C, 63.3; H, 5.6.%

c. 2-( 3-Chloro-2-hydroxypropoxy)-6-hydroxyacetophenone A mixture of 10parts of 2,6-dihydroxyacetophenone, 7 parts of epichlorohydrin in 18parts (by volume) of dioxan and 5 drops of Triton B, was heated at 100Cin a sealed vessel for 2% days. The solvent was then removed underreduced pressure and an excess of ether was added to the residue. Theother solution was decanted from the insoluble, washed with water (2 X50 parts) and 2N sodium carbonate (3 X 25 parts). The solvent wasremoved after drying over sodium sulphate and the residue was purifiedby chromatography using an alumina column and other as eluent. The oilwas distilled to obtain 2-(3-chloro-2-hydroxypropoxy)-6-hydroxyacetophenone (6 parts) as a yellow oil b.p.166-8 at 1.5mm. Analysis: Found: C, 53.7; H, 5.26% C H ClO, requires: C,54.0; H, 5.32% d. 1-( 2-Acetyl-3 -hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane To the above chlorohydrin (6 parts) wasadded 3.8 parts of resacetophenone,3.5 parts of anhydrous potassiumcarbonate and 50 parts (by volume) of dry acetone. This mixture wasrefluxed for 2 days. Then the insoluble material was filtered, aftercooling, and stirred in water to remove inorganic material.Recrystallization of the residue from dioxan yielded 0.7 parts of1-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane melting between 182 and 185C andidentical with the product from b above. From the acetone filtrate afurther 2 parts of this product were obtained. e. 12-Ethoxycarbonylchromon-5-yloxy )-3-(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane By the method ofExample lbl-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-3-hydroxyphonoxy)-2-hydroxypropanewas condensed with diethyl oxalate to form 12-ethoxycarbonylchromon-5-yloxy )-3-(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane melting between 193and 194.5C from ethanol plus dioxan. Analysis: Found: C, 63.0; H, 4.3%

with preliminary softening. Analysis:

a C 7H2 On requires: C, H, f. 1-(2-Carboxychromon-5-yloxy )-3-(2-carboxychromon-7-yloxy)-2-hydroxypropane The ester from e above washydrolyzed as in Example 5c to obtain the acid melting Found: C, 55.2;H, 3.96% C H O H O requires: C, 54.7; H, 3.9%

This acid was dissolved in an equivalent amount of sodium bicarbonatesolution and freeze-dried to obtain the disodium salt.

si ler;

dihydroxy acetophenone, l,5-bis(2-aeetyl-3-hydroxyphenoxy)pentane andsuspected 2-(5-bromopentyloxy)-6-hydroxyacetophenone to be present. Theacetone solution was concentrated'to half its volume and the residue wasremoved by filtration. After washing with water this residue yielded 1.9parts of 1,5-bis(2-acetyl- 3-hydroxyphenoxy)pentane. The filtrate wastaken to dryness and chromatographed on an alumina column using ether aseluent. The 2-(5-bromopenty1oxy)-6- hydroxyacetophenone came ofi in thefirst fractions, as confirmed by thin layer chromatography. Evaporationof these collected fractions yielded 5 parts as an oil which was used asfollows without further purification. Thus a mixture of 2.4 parts of thecrude oil, 1.2 parts of resacetophenone, 1 part of anhydrous potassiumcarbonate and 40 parts (by volume) of dry acetone was refluxed for 20hours. After cooling the acetone solution was filtered and evaporated todryness. The residue was crystallized from methanol-water to yield 1.85parts of l-(2-acetyl-3-hydroxyphenoxy)-5-(4-acetyl-3-hydroxy-phenoxy)pentane melting between 91 and 915C.

Analysis:

- Found: C, 67.3; H, 6.7%

off and the residue was taken up in water and filtered,

the filtrate was then acidified with dilute hydrochloric acid. The solidwhich separated proved difiicult to filter between 194 and 200C.

22 and was, therefore, separated frorn tlie liquors by centrifuging,washing twice with water and recentrifuging. The1-(2-carboxychromon-5-yloxy)-5-(2-carboxychromon-7-yloxy)pentane (0.25parts) was crystallized from ethanol and had a melting point between 249and 25 1C with preliminary softening.

Analysis: Found: C, 60.3; H, 4.4% c,,H,,o,,.H,o requires: C, 60.2; H,4.45%

This acid was dissolved in an equivalent amount of sodium bicarbonatesolution and freeze-dried to obtain the disodium salt.

EXAMPLE 18 hours; after cooling 250 parts of water were added and I thesolid was isolated by filtration. Crystallization of this solid fromethanol yielded 4.15 parts of 1,3-bis(2-acetyl-3-hydroxy-5-methylphenoxy)-2-hydroxypropane melting between 185and 186C. Analysis: Found: C, 64.1; H, 6.3% C l-1 0., requires: C, 64.9;H, 6.2% b. l ,3-Bis( 2-carboxy-7-methylchromon-5-yloxy)-2-hydroxypropane By the method of Example 1b the above compound wascondensed with diethyl oxalate to yield 1,3-bis(2ethoxycarbonyl-7-methylchromon-5-yloxy)-2-hydroxypropane crystallizingfrom ethanol as colourless needles melting between 194 and 196C. Theester was hydrolyzed as in Example 50 to obtain the acid as themonohydrate crystallising from aqueous dioxan and melting between 240and 241C. Analysis: Found: C, 58.3; H, 4.4% C H O H O requires: C, 58.4;H, 4.3%

The acid was subsequently converted to the disodiurn salt by the methodof Example 5c.

EXAMPLE 19 a. 1 ,3-Bis( 2-acetyl-4-ethy1-3-hydroxyphenoxy)-2-hydroxypropane 2,6-Dihydroxy-3-ethylacetophenone was condensed withepichlorohydrin by the method of Example 18a. to yieldl,3-bis(2-acetyl-4-ethyl-3-hydroxyphenoxy)-2- hydroxypropane meltingbetween and 137C. (from ethanol). Analysis: Found: C, 66.7; H, 6.9% Ci-1 0 requires: C, 66.3; H, 6.8% b. 1 .3-Bis(2-carboxy-8-ethylchromon-5-yloxy)-2- hydroxypropane The above compoundwas condensed with diethyl oxalate as in Example 1b. to obtain 1,3-bis(2-ethoxycarbonyl-8-ethylchromon-5-yloxy)-2-hydroxypropane meltingbetween 159 and 161C (from ethanol).

This ester was hydrolyzed as in Example 5c to obtain the acid as thedihydrate crystallizing from ethanol and melu'ngbetween 193 and 194C 23Analysis: Found: C, 57.5; H, 4.9% C H,,,,O, .2H O requires: C, 57.85; H,3.0% The disodium salt was then prepared as in Example EXAMPLE 20 12-Carboxychromon-5-yloxy)-3-(2-carboxy-8-ethylchromon-S-yloxy)-2-hydroxypropane 2,6-Dihydroxy-3-ethylacetophononewas condensed with 2-(2,3-epoxypropoxy)-6-hydroxyacetophonone as inExample 16b to yield l-(2-acetyl-3-hydroxyphenox-' y)-3(2-acetyl-4-ethyl-3-hydroxyphonoxy)-2-hydroxypropane melting between 102and 103C, from aqueous ethanol.

Analysis:

Found: C, 64.8; H,6.3%

C H O requires: C, 64.9; H, 6.2%

This diketone was condensed with diethyl oxalate using the method ofExample 1b and 1-(2-ethoxycarbonylchrornon-5-yloxy)- 3-(2-ethoxycarbonyl-8- ethylchromon-5-yloxy)-2-hydroxypropane was obtained,1 melting between 166 and 166.5C from ethanol.

Analysis: Found: C, 62.6; H, 4.95% C I-15 requires: C, 63.0; H, 5.1%

The ester was hydrolyzed as in Example 50 to yield the acid dihydratemelting between 190 and 192C from ethanol. Analysis:

Found: C, 56.8; H, 4.4% C H O .2H2O requires: C, 56.4; H, 4.5%

The disodium salt was prepared as in Example c.

EXAIVIPLE 21 1 .5-Bis(2-carboxychromon-8-yloxy )pentane2,3-Dihydroxyacetophenone was condensed with 1,5-dibromopentane usingthe method of Example la to obtainl,5-bis(2-hydroxy-3-acetylphenoxy)pentane, melting between 103.5 and104.3C, (from ethanol). Analysis: Found: C, 67.7; H, 6.9% C H Orequires: C, 67.7; H, 6.5

This ketone was condensed with diethyl oxalate as in Example 1b to yield1,5-bis(2-ethoxycarbonylchromon-S-yloxy) pentane melting between 128 and1 30 (from ethanol).

Analysis:

EXAMPLE 22 1 ,5-Bis( 2-carboxy-6-methylchromon-7-yloxy)pentane2,4-Dihydroxy-3-methylacetophenone was condensed with 1,5-dibromopentaneusing the method of Example la to yield l,5-bis(4-acetyl-3-hydroxy-2-methylphenoxy)pentane melting between 116 and 153C. Analysis:

The ester was hydrolyzed using the method as in Example So to obtain theacid melting between 274 and 276 from dioxan.

Analysis:

Found: C, 63.0; H, 5.0%

C H O requires: C, 63.8; H, 4.8%

The disodium salt of this acid was prepared as in Example 5 (c EXAMPLE2? 1 ,3-Bis( 2-carboxy-8-methylchromon-7-yloxy)-2- 25 hydroxypropane2,4-Dihydroxy-3-methylacetophenone was condensed with epichlorohydrin bythe method of Example 18a and after crystallising from ethanol,1,3-bis(4- acetyl-3-hydroxy-2-methylphenoxy)-2-hydroxypropane wasobtained melting between 151 and Found: C, 64.8; H, 6.25% C H Orequires: C, 64.9; H, 6.2%

This ketone was then condensed with diethyl oxalate as described inExample 1b to yieldl,3-bis(2-ethoxycarbonyl-8-methylchromon-7-yloxy)-2-hydrox- 1 plusethanol).

Analysis: Found: C, 63.0; H, 5.24%

C H O requires: C, 63.0; H, 5.1%

Found: C, 56.7; H, 4.35%

The above ester was hydrolyzed as in Example 5c to give1,3-bis(2-carboxy-6-methylchromon-7-yloxy)-2- hydroxypropane dihydratemelting between 272 and 275C.

Analysis:

C l-l O .2H O requires: C, 56.4; H, 4.5%

The disodium salt of the acid was prepared as in Example 5c.

EXAMPLE 24 1 ,5-Bis( 2-carboxychromon-5 -yloxy)-3-methylpentane2,6-Dihydroxyacetophenone was condensed with l,5-dibromo-3-methylpentaneby the method described in Example 1a to give 1,5-bis(2-acetyl-3-hydroxyphonoxy)-3-methylpentane melting between 123 and 124C (fromethanol).

1 Analysis: Found: C, 68.8; H, 6.9%

25 C l-1, 0, requires: C, 65.4; H, 5.5%

Hydrolysis of the above ester by the method described in Example c'yielded after crystallization from aqueous ethanol l,5-bis(2-carboxychromon-5- yloxy)-3-methylpentane monohydrate melting between2l5and 217C.

Analysis: Found: C, 61.6; H, 4.8% c n o n o requires: C, 60.9; H, 4.7%

This acid was converted to its disodium salt by the method described inExample 5c.

EXAMPLE 25 1,3-Bis( 2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropane. Disodium salt 2,4-Dihydroxy-5-chloroacetophenone wascondensed with epichlorohydrin using the method as described in Example18a to yield, after crystallization from n-propanel,1,3-bis(4-acetyl-2-chloro-5-hydroxyphenoxy)-2-hydroxypropane meltingbetween 197 and 199C.

Analysis:

Found: C, 52.6; H, 4.7%

C H Cl O requires: C, 53.1; H, 4.2%

The ketone was condensed with diethyl oxalate as described in Example lbto yield after crystallization from ethanol, 1 ,3-bis(2-ethoxycarbonyl-6- chlorochromon-7-yloxy)-2-hydroxypropane meltingbetween 199 and 202C.

Analysis: Found: C, 54.7; H, 3.6% C H CI O requires: C, 54.6; H, 3.7%

This ester was hydrolyzed using the method described in Example 10 andthe disodium salt of 1,3-bis(2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropane tetrahydrate wasobtained from aqueous ethanol.

EXAMPLE 26 1 Z-Carboxychromon-S-yloxy )-3-( 2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropane. Disodium salt2,4-Dihydroxy-5-chloroacetophenone was condensed with2-(2,3-epoxypropoxy)-6-hydroxyacetophenone as in Example 16b to givel-(2-acetyl-3-hydroxyphenoxy)-3-(4-acetyl-2-chloro-5-hydroxyphenoxy)-2-hydroxypropanemelting between 139 and 140C.

This diketone was condensed with diethyl oxalate as described in Example1b to yield after crystallization from ethanol1-(2-ethoxycarbonylchromon-5-yloxy)-3-(2-ethoxycarbonyl-6-chlorochromon-7-yloxy)-2- hydroxypropane meltingbetween 166 and 168C. Analysis:

Found: C, 57.4 ;H, 4.3% C27H23Cl 01 requires: C, H,

This ester was converted to the disodium salt using the method asdescribed in Example 10 to give from aqueous ethanol the disodium saltof 1-(2-carboxychromon-5-yloxy)-3-(2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropane tetrahydrate.

Analysis: Found: C, 45.5; H, 2.9% C H ClNa O 4H O requires C, 44.6; H,3.4%

EXAMPLE 27 1 ,5-Bis( 2-carboxychromon-6-yloxy )pentane Quinacetophenonewas condensed with 1,5- dibromopentane using the method described inExample 1a to obtain 1,5-bis( 3-acetyl-4-hydroxyphenoxy)pentane meltingbetween 107 and 109C, from ethanol.

Analysis: Found: C, 67.8; H, 6.8% C l-1 0 requires: C, 67.7; H, 6.5%

The diketone was condensed, using the method as in Example 1b, withdiethyl oxalate to yield 1,5-bis(2-ethoxycarbonylchromon-6-yloxy)pentane.

Analysis: Found: C, 64.7; H, 5.5% C H O requires: C, 64.9; H, 5.3%

This ester was hydrolyzed using the method described in Example 5a andyielded, after crystallization from dioxan,1,5-bis(2-carboxychromon-6-yloxy)pentane melting between 275 and 277C.

Analysis: Found: C, 62.6; H, 4.5% c,,H,,o,, requires: C, 62.5; H, 4.2%

This acid was converted to its disodium salt by the method described inExample 5c.

EXAMPLE 28 1 ,3-Bis( 2-carboxychromon-7-yloxy)-2-hydroxypropaneResacetophenone was condensed epichlorohydrin as in Example 18a to give1,3-bis(4- acetyl-3-hydroxyphenoxy)-2-hydroxypropane melting between 152and 154C (from ethanol).

Analysis: 1 Found: C, 63.5; H, 6.2% C H O requires: C, 63.3; H, 5.6%

1 ,3-Bis( 4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane was condensed withdiethyl oxalate using the method as described in Example 1b to obtain1,3-bis(2- ethoxycarbony]chromon-7-yloxy)-2-hydroxypropane meltingbetween 178 and 180C (from aqueous dioxan).

Analysis: Found: C, 62.2; H, 4.5% C T-1 ,0, requires: C, 61.8; H, 4.6%

The ester was hydrolyzed as in Example 50 to yield, aftercrystallization from dioxan-water, 1,3-bis(2-carboxychromon-7-yloxy)-2-hydroxypropane monohydrate melting between155 and C. Analysis:

Found: C, 56.8; H, 3.7% C H O ,.H O requires: C, 56.8; H, 3.7%

The disodium salt of this acid was prepared as in Example 5c.

EXAMPLE 29 1 ,2-Bis( 2-carboxychromon-5-y1oxymethy1)benzene1,2-Bis(bromomethyl)benzene was condensed with 2,6-dihydroxyacteophenone as described in Example 10 to give, aftercrystallization from ethanol, 1,2-bis( 2-acetyl-3-hydroxyphenoxymethyl)benzene melting between 148 and 153C.

Analysis:

Found: C, 70.5; H, 5.4%

C l-I 0 requires: C, 70.9; H, 5.5%

The diketone was condensed with diethyl oxalate as in Example 1b toyield 1,2-bis(2-ethoxycarbonylchromon-S-yloxymethyl)benzene meltingbetween 204 and 206C.

with

. Analysis: Found: C, 68.1; H, 4.55% C H O requires: C, 67.4; H, 4.6%

This ester was saponified using the method as described in Example toobtain the disodium salt as the tetrahydrate. Analysis:

Found: C, 54.0; H, 3.3%

C,,H,,Na,O .4l-l,O requires: C, 53.3; H, 3.8%

EXAMPLE 30 l ,3-Bis( Z-carboxychromon--yloxy)-2-hydroxypropane.

Quinacetophenone was condensed with epichlorohydrin as described inExample 18a to obtain after crystallization from aqueous methanoll,3-bis( 3- acetyl-4-hydroxyphenoxy)-2-hydroxypropane melting between127 and 129C.

Analysis: Found: C, 62.6; H, 5.7% C H O, requires: C, 63.3; H, 5.6%

This ketone was condensed as described in Example lb with diethyloxalate to yield l,3-bis(2-ethoxycarbonylchromon-6-yloxy)-2-hydroxypropane melting between 187 and 189C(from ethanole-dioxanwater).

Analysis: Found: C, 62.0; H, 4.3% C H O requires: C, 61.8; H, 4.6%

Hydrolysis of this ester using the method described in Example 170 gave1,3-bis(2-carboxychromon-6-yloxy)-2-hydroxypropane dihydrate meltingbetween 268 and 270C (from ethanol-dioxan-water).

Analysis: Found: C, 55.0; H, 3.3% C H O lH O requires: C, 54.7; H, 3.9%

The disodium salt of this acid was prepared as described in Example 50.

EXAMPLE 31 Disodium salt of l-(2-carboxychromon-5-yloxy)-3-( 2-carboxychromon-6-yloxy)-2-hydroxypropane Quinacetophenone was condensedwith epichlorohydrin as described in Example 16a to yield, aftercrystallization from petrol (b.p. 60-80C), 5-(2,3-epoxypropoxy)-2-hydroxyacetophenone melting between 76 and 79C.

Analysis: Found: C, 64.0; H, 5.6% C H Q, requires: C, 63.45: H, 5.8%

This epoxide was condensed with 2,6-dihydroxyacetophenone as in Example16b to yield 1-(2-acetyl-3-hydroxyphenoxy)-3-(3-acetyl-4-hydroxyphenoxy)-2- hydroxypropanemelting between 185 and 186C, after crystallization from ethanol.

Analysis: Found: C, 63.5; H, 5.6% C ,,H O requires: C, 63.3; H, 5.6%

This compound was condensed with diethyl oxalate as in Example 1b andafter crystallization from ethanol, 1 2-ethoxycarbonylchromon-5 -yloxy)-3-(2-ethoxycarbonylchromon-6-yl0xy)-2-hydroxypropane obtained meltingbetween 164 and 166C. Analysis: C, 62.4; H, 4.5%

C H O requires: C, 61.8; H, 4.6%

This ester was hydrolyzed to the disodium salt using the methoddescribed in Example 10.

was

2s EXAMPLE 32 Disodium salt of 1-(2-carboxychromon-5-yloxy)-3-( 2-carboxychromon-8-yloxy)-2-hydroxypropane.

2-( 2,3-Epoxypropoxy)-6-hydroxyacetophenone was condensed with2,3-dihydroxyacetophenone by the method described in Example 16(b) togive, after crystallization from ethanol plus dioxan, 1-(2-acetyl-3-hydroxyphenoxy)-3-(3-acetyl-2-hydroxyphenoxy )-2- hydroxypropane meltingbetween 166 and 169C. Analysis:

Found: C, 63.6; H, 5.7% C,,H,,O-, requires: C, 63.3; H, 5.6%

After condensation with diethyl oxalate, as in Example lb, this compoundgave l-(2-ethoxycarbonylchromon-5-yloxy)-3-(2-ethoxycarbonylchromon-8-yloxy)-2-hydroxypropane melting between 162 and C, (from ethanol),

Analysis: Found: C, 61.6; H, 4.75% C H O requires: C, 61.8; H, 4.6%

This ester was saponified as described in Example 10 and the disodiumsalt was obtained.

EXAMPLE 3 3 l ,8-Bis( 2-ca.rboxychromon-5 -yloxy )octane2.6-Dihydroxyacetophenone was condensed with 1.8-dibromooctane as inExample 1a to give 1,8-bis( 2- acetyl-3-hydroxyphenoxy)octane meltingbetween 107 and 109C, from benzene.

Analysis:

Found: C, 69.6; H, 7.25%

C H O requires: C, 69.5; H, 7.3%

This diketone was reacted with diethyl oxalate in the usual manner(Example lb to obtain after crystallization from ethanol,1,8-bis(2-ethoxycarbonylchromon-5 -yloxy)octane melting between 139 and141C. Analysis:

Found: C, 66.0; H, 6.0% C H O requires: C, 66.4; H, 5.0%

Hydrolysis of this ester as in Example 5c yielded 1,8-bis(2-carboxychromon-5-yloxy)octane monohydrate of indefinite meltingpoint.

Analysis: Found: C, 61.1; H, 5.4% C H O H O requires: C, 62.2; H, 5.2%

The disodium salt of this compound was prepared as in Example 50.

EXAMPLE 34 l ,9-Bis( 2-carboxychromon-5 -yloxy )nonane2,6-Dihydroxyacetophenone was condensed with 1,9-dibromononane as inExample 1a to yield 1,9-

bis(2-acetyl-3-hydroxyphenoxy)nonane melting between 55-5 9C aftercrystallizing from ethanol.

Analysis:

Found: C, 69.7; H, 7.5%

c H O requires: C, 70.1; H, 7.5%

This diketone with diethyl oxalate gave, using the method of Example 1b,1,9-bis(2-ethoxycarbonylchromon-S-yloxy) nonane crystallizing fromethanol and melting between 128 and 129C.

Analysis: Found: C, 66.4: H, 6.2% C H O requires: C, 66.9; H, 6.1%

Hydrolysis of this ester as in Example 5c yielded 1,9-bis(2-carboxychromon-5-yloxy)nonane, crystallizing EXAMPLE 35 l ,2-Bis(2-carboxychromon-5-y1oxy)ethane 2,6-Dihydroxyacetophenone was condensedwith 1,2-dibromoethane using the method of Example la to obtain 1,2-bis( 2-acetyl-3-hydroxyphenoxy )ethane melting between 188 and 189after crystallization 1 from acetic acid.

Analysis: Found: C, 65.7; H, 5.4% C H O requires: C, 65.4; H, 5.5%

The condensation of this compound with diethyl oxalate was carried outas in Example 1b to yield after crystallization from. dioxan1,2-bis(2-ethoxyca.rbonylchromon-5-yloxy)ethane melting between 264 and265C. Analysis: Found: C, 63.0; H, 4.7% C H O requires: C, 63.15; H,4.5%

This ester was hydrolyzed using the method as in Example 170 to, give1,2-bis(2-carboxychromon-5-ylox- 1 y)ethane melting between 262 and263C.

- Analysis:

Found: C, 59.6; H, 3.1% C H O requires: C, 60.3; H, 3.2%

The disodium salt of this acid was prepared in the manner described inExample 50.

Example 36 1 ,3-Bis( 2-carboxychromon-5 -yloxy)-2-chloromethyl-2-hydroxymethylpropane; dipotassium salt tetrahydrate2,6-Dihydroxyacetophenone was condensed with3,3-bis(chloromethyl)oxetane using the method as described in Example lato give 3,3-bis(2-acetyl-3- hydroxyphenoxymethyl)oxetane melting between209 and 21 1C. Analysis: Found: C, 65.3; H, 5.75% C H O requires: C,65.3; H, 5.7%

This oxetane (7 parts), 2 parts (by volume) of concentrated hydrochloricacid, 10 parts of water and 25 Found: C, 59.0; H. 4.7% C H CIO requires:C, 59.3; H,4.6%

' Analysis:

To 0.8 parts of the ester in' 30 parts (by volume) of methanol was added3.15 parts of a 0.87N solution of potassium hydroxide in methanol. Thissolution was heated under reflux for 10 minutes, decolorized withcharcoal, filtered and reduced in volume by evaporation until on cooling0.6 parts of the dipotassium salt of 1 ,3-bis( 2-carboxychromon-5-yloxychloromethyl-2- hydroxymethylpropane tetrahydrate crystallized.Analysis:

Found: C, 44.4; H, 3.4%

C H ClK O H O requires: C, 44.3; H, 3.9%

EXAMPLE 37 Disodium salt of l,3-bis(2-carboxychromon-5-yloxy)-2-ethoxypropane 1 l ,3 -Bis( 2-carboxychromon-5-yloxy)-2-hydroxypropane, diethyl ester, 15 parts, was suspended in parts ofethyl iodide and 10 parts of freshly prepared silver oxide was addedwith stirring. The stirred suspensiorl was heated under reflux for fourdays. The solids were then filtered, washed with cold ethanol and thenextracted with boiling ethanol in a Soxhlet extractor to obtain 9.7parts of a mixture of starting material with the required ethyl ether.This was separated by chromatography on a silica gel column usingchloroform as eluent, to obtain 20 percent by weight of the pure diethylester of 1,3-bis(2-carboxychromon-5-yloxy)-2- ethoxypropane meltingbetween 192 and 193C. Analysis: Found: C, 63.1; H, 5.06% cggl'lzgorequires: C, 63.0; H, 5.07%

By the method of Example 10 this ester was converted to the disodiumsalt. Analysis: Found: C, 52.2; H, 3.32% C H Na O .2H O requires: C,52.1; H, 3.85%

EXAMPLE 3 8 Disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-oxypropane A mixture of 4 parts diethyl ester of1,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane, 16 parts aceticanhydride and 24 parts dimethyl sulphoxide was ground in a revolvingglass jar containing glass beads for 3 days. The mixture was then heatedto C.. for 2 hours and filtered while still warm. The solid was washedwith ethanol and recrystallized from a mixture of chloroform and petrolto obtain 1.2 parts of the diethyl ester of1,3-bis(2-carboxychromon-5-yloxy)-2- oxopropane melting at 210C.

Analysis: Found: C, 61.6; H, 4.61% C H O requires: C, 62.1; H, 4.21%

By the method of Example 1c part of this ester was converted to thesodium salt.

Analysis:

Found: C, 48.1; H, 2.80; Na, 7.85% C H, Na O ,,4.H O requires: C, 7 .4;H, 3.43; Na, 7.9%

EXAMPLE 39 a. 2,5-Bis( 2- acetyl-3-hydroxyphenoxymethyl)dioxana'zeotrope. A solution of 15 parts of 2,5-bis,iodomethyldioxan in 50parts of isopropanol was added and the mixture heated, with stirringunder reflux for 3 days. The solvent was distilled off and water added.The mixture was extracted with chloroform which was then evaporated toleave a rod oil. This was extracted with boiling ether to leave 1 partof '2,5-bis(2-acetyl- 3- hydroxyphenoxy methyl)-dioxan as an orangesolid melting between 230 and 232C. Analysis: Found: C, 63.7; H, 5.89% CH O requires: C, 63.5; H, 5.77% b. Diethyl ester of2,5-bis(2-carboxychromon-5-yloxymethyD-dioxan 1 As in Example lb 1 partof 2,5-bis(2-acetyl-3- hydroxyphenoxy methyl)dioxan was reacted withdiethyl oxalate as far as the isolation of the sodium salt of the diketoester. This was suspended in water and acidified with acetic acid toobtain an orange solid melting between 176 and 177C. This wasrecrystallized from a mixture of ethanol and benzene to obtain a firstcrop of 0.3 part solid melting between 192 and 194C and which thensolidified and remelted between 274 and 278C. Analytical data andinfra-red spectra suggest this product to be the diethyl ester ofl,6-bis( 2-carboxychromon-S-yloxy)-2-hydroxy-5-hydroxymethyl-4-oxahexane producedby ring opening of the dioxan ring. A second crop of a solid meltingbetween 276 and 280C was obtained by concentrating the fltrate. This waspurified by recrystallization from ethanol to obtain 0.2 part of thediethyl ester of 2,5- bis(2-carboxychromon-5-yloxymethyl)dioxan meltingat 285C with decomposition.

Analysis:

Found: C, 62.3; H, 4.61%

G l-1 requires: C, 62.1; H, 4.83%

EXAMPLE 40 l ,5-Bis-( 2-carboxychromon-5-yloxy )-pentane A mixture of 37parts of 1,5-bis(2-acetyl-3-hydroxyphenoxy) pentane and 52 parts byweight of ethyl ethoxydichloroacetate (80 percent purity) was heated at150-170 for 5-hours. After evaporating under reduced pressure themixture thus obtained, which contained the diethyl ester of the desiredacid, was dissolved in acetic said containing 17 percent concentratedhydrochloric acid. This solution was boiled under reflux for 4 hours.After cooling the solid was filtered off, washed with water andcrystallized from ethanol to yield1,5-bis(2-carboxychromon-5-yloxy)pentane monohydrate melting between 226and 228 and shown to be identical with the material prepared in Example6.

EXAMPLE 41 l ,5-Bis( 2-carboxychromon-5 -yloxy)pentane' To a mixture ofparts of l,5-bis(2-acetyl-3- hydroxyphenoxy)pentane and 20 parts ofpyridine cooled in ice was slowly added 13 parts of ethyloxalylchloride. The mixture was then allowed to stand for 24 hours andthen heated at 100 for 30 minutes. After cooling, and pouring ontomixture of ice and excess of concentrated hydrochloric acid an oil wasformed which was extracted with chloroform, washed, and the chloroformsolution was driedover sodium sulphate. After filtration and removal of.the solventthe residue was crystallized from ethanol to give the diethylester of 1,5-bis(2-carboxychromon-5-yloxy)pentane melting between 150and 152 and shown to be identical with a sample as prepared in Example6.

EXAMPLE 42 a. l,5-Bis( 2-methylchromon-5-yloxy)pentane.

A mixture of 4.6'parts of powdered-sodium, 7.44 parts of1,5-bis(2-acetyl 3 hydroxyphenoxy)pentane and 150 parts of ethyl acetatewas heated for 2% hours with stirring.

The resulting orange solution was cooled and diluted with 400 parts ofether. The precipitated solid was extracted'with water and the extractwas acidified with dilute hydrochloric acid. The precipitated oil wasextracted with chloroform and the chloroform solution was dried overanhydrous sodium sulphate, filtered,

and the solvent was then removed to yield a red oil.

This oil was heated under reflux with ethanol and 0.5 parts ofconcentrated hydrochloric acid for 10 minutes. The solution wasevaporated to leave an oil which was triturated with ether and theresulting solid was collected. This solid was crystallized from amixture of ethyl acetate and petroleum ether (b.p. 4060C) to give 4.82parts of l,5-bis( 2-met'hylchromon-5-yloxy)pentane, melting point l403C.The ether wash afforded a further 0.4 parts of the same material.Analysis: Found: C, 71.00; H, 5.87% C H O requires: C, 71.41; H, 5.75%b. 1,5-Bis( 2-carboxychromon-5-yloxy)pentane To a mixture of 5 parts of1,5-bis(2.-methylchromon- 5-yloxy) pentane in parts of dioxan was added6 parts of finely divided selenium dioxide and the mixture was heatedunder reflux for 6 hours. After cooling, the precipitated selenium wasfiltered off and the solvent was removed from the filtrate under vacuum.The residue was dissolved in chloroform and the chloroform was extractedwith sodium bicarbonate solution. The crude product was precipitatedupon addition of hydrochloric acid to the alkaline extract and it wascrystallized from ethanol to yieldl,5-bis(2-carboxychromon-5-yloxy)pentane as the monohydrate meltingbetween 226 and 228, identical with the material prepared in Example 6.

EXAMPLE 43 a. 1,5-Bis(Z-styrylchromon-S-yloxy)pentane A solution ofsodium ethoxide was prepared from 0.294 parts of sodium and 8.0 parts ofethanol. ,To this was added with stirring over 10 minutes a mixture of1.5 parts of benzaldehyde and 2.7 parts of 1,5-bis(2-methylchromon-S-yloxy)pentane in 35 parts of ethanol. The mixture wasstirred and heated under reflux for 4 hours and then allowed to stand atroom temperature for 16 hours.

The brown oily solid which had precipitated was filtered off andtriturated with ether. The resulting solid was filtered off anddissolved in glacial acetic acid. The solution was treated withcharcoal, filtered, and diluted with water to give 1.55 parts ofl,5-bis( 2- styrylchromon-S-yloxy)pentane, melting point 2 l 7-22 0C.

under reflux 3i. Analysis: Found: C, 77.4; H, 5.87% C H O requires: C,78.50; H, 5.41% b. l,5-Bis(2-carboxychromon-5-yloxy)pentane A solutionof 10 parts of potassium permanganate in 200 parts of water was added toa solution of parts of 1,5-bis(2-styrylchromon-5-yloxy)pentane in 50parts of pure pyridine. The mixture was stirred at room temperature forseveral hours. The presence of excess of potassium permanganate waschecked from time to time and further amounts of a 5 percent aqueoussolution of potassium permanganate were added as I required. When nofurther oxidation took place the solution was acidified withhydrochloric acid and sulphur dioxide was passed to decolorize. Theprecipitated material was filtered off, washed with hot water andextracted with sodium bicarbonate solution.

On'acidification the product was precipitated and was filtered off,dried, and crystallized from ethanol to yield 1 ,5bis(2-carboxychromon-5-yloxy )pentane monohydrate melting between 226 and228 and shown to be identical with the material prepared in Example 6.

EXAMPLE 44 l ,3-Bis( 2-ethoxycarbonylchromon-7-yloxy )-2-hydroxypropaneA solution of sodium ethoxide was prepared from 0.115 parts of sodiumand30 parts of ethanol. To this was added a mixture of 2.34 parts ofethyl-7-hydroxychromon-2-carboxylate and 0.462 parts of epichlorohydrin.The mixture was stirred and heated under reflux for 4 hours.

Half of the ethanol was evaporated off and the remaining mixture wasdiluted with 300 parts of water. The aqueous solution was then extractedwith chloroform. The organic solution was dried over anhydrous sodiumsulphate, filtered, and evaporated to leave a red oil. The mellow solidobtained by tn'turation of this oil with ethanol was filtered off andwashed with alcohol giving 0.12 parts ofl,3-bis(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane, melting point178-9C. The identity of the product with a sample as prepared in Example28 was confirmed by a mixedmelting point determination, by thin layerchromatography, and by infra-red analysis.

EXAMPLE 45 A solution of 5.7 parts of 1,5-dibromopentane in 50 parts ofethanol was added to a solution of 5.6 parts of potassium hydroxide and33 parts of hydroquinone in 40 parts of ethanol. The mixture was heatedunder reflux for 16 hours, then the ethanol was evaporated off and themixture was diluted with 200 parts of water, solidified withconcentrated hydrochloric acid and the resulting precipitate wasfiltered off. The solid thus obtained was extracted with hot benzene andthe solution was treated with charcoal and filtered while hot. Thesolution on cooling, yielded 4.9 parts of l,5-bis(4-hydroxyphenoxy)pentane melting point 1 l0-12. Analysis:

I Found: C, 71.7; H, 7.14%

C H O requires: C, 70.8; H, 6.99%

5.8 parts of l,5-bis(4-hydroxyphenoxy)pentane were treated with asolution of 1.6 parts of sodium hydroxide in parts of water. Water wasevaporated from the mixture and the solid was dried in an oven at 100.The

solid was treated with 50 parts of dioxan and the mixture was stirredand heated under reflux. Subsequently, 6.8 parts of diethylacetylenedicarboxylate were added dropwise to the mixture, which wasstirred and heated under reflux for 50 minutes. The mixture was cooledand acidified with 20 percent v/v sulphuric acid, then the mixture wastreated with 25 parts of 25 percent sodium hydroxide solution and heatedunder reflux for 50 minutes. The mixture was cooled, acidified with 20percent v/v sulphuric acid and dioxan was distilled off. The resultingprecipitate was filtered ofl and was extracted with sodium bicarbonatesolution. The extract was acidified with dilute sulphuric acid and theresulting precipitate was filtered ofi and dried in air to give 10.4parts of a light colored solid, which was crushed with 30 parts ofconcentrated sulphuric acid. The mixture was allowed to stand for 40minutes and then it was filtered through a plug of glass-wool. Thefiltrate was filtered off, washed with water and crystallized fromaqueous dioxan to give 1.5 parts ofl,5-bis(2-carboxychromon-6-yloxy)pentane melting point 270l, shown to beidentical with the material prepared in Example 27.

EXAMPLE 46 The activity of the now his chromonyl compounds has beenevaluated by the antigen inhalation test on human volunteers who sufi'erfrom specific allergic asthma. The degree of asthma provoked by theinhala-.

tion of an antigen to which the volunteers are sensitive can be measuredby repeated estimation of the increase of air way resistance.

A suitably designed spiromotor was used to measure the forced expiratoryvolume at 1 second (REV. 1.0), and hence the changes in the air wayresistance. The anti-allergic activity of compound is estimated from thedifference between the maximum percent F.E.V. l .0 reduction followingcontrol and test provocations after drug administration conducted underidentical experimental conditions.

Thus:

% protection Av. max. F.E.V. -Max. F.E.V. fall control shock full testshock [REMFTEYVQQ fall'contml snack The compounds under test wereadministered as an aerosol by inhalation for 5 minutes, 2 hours beforechallenge with antigen. The compounds for administration were dissolvedin sterile water at a concentration of 0.5 percent and aerosolized froma Wright nebulizer operating at 10 liters/minute air flow, giving atotal weight of drug aerosolized of 5 mg. The following table shows theprotection obtained with a number of the new bis-chromonyl compounds.

yloxy)-docunc.

Disodium salt of l,6-bis(2-carboxychromon-6- yloxy)-hexane. 45-50Disodium salt of l.3-bis(2-carboxychromon-5- yloxy)-2-l1ydroxypropane.65-70 Disodium salt of l,3-bis(2-carboxychromon-5- yloxy )-propane 40-45Disodium salt of l,5-bis(2-carboxy-8-chlorochromon-S-yloxy )pentane.20-25 Disodium salt of l,5-bis(2-carboxychromon-6- yloxy)-pentanc. 20-25Disodium salt of l,5-bis( 2-carboxychromon-7- yloxy)-pentane. 45-50Disodium salt of l,3-bis(2-carboxychromon-7- yloxy)-2-hydroxypropane.40-45 Disodium salt of l,3-bis( Z-carboxy-S-ethylchromon-S-yloxy)-2-hydroxypropane. 20-25 Disodium salt of l,2-bis(2-carboxychromon-5-yloxymethyD-benzene. 30-35 Disodium slat of l-(Z-carboxychromon-S-yloxy)-3-(2-carboxychromon-7-yloxy)-2-hydroxypropane. 45-50 Disodium salt ofl,3-bis( Z-carboxychromon-fi yloxy)-2-hydroxypropane. 40-45 Disodiumsalt of l,3-bis(2-carboxy-8- methylchromon--7-yloxy)-2-hydroxypropane. 1-20 Disodium salt of l-(2-carboxychromon-5-yloxy )-3-(2-carboxy-8-ethyl-chromon-5-yloxy)-2-hydroxypropane. 25-30Dipotassiuniialt of l,3-bis( Z-carboxychromon-S- yloxy)-2-chloromethyl-2-hydroxymethylpropane. 40-45 Disodium salt of l,5-bis(Z-carboxychromon-S- yloxy)-3-methylpentane. 20-25 Disodium salt ofl-(2-carb0xychromon-5-yloxy)-3- (2-carboxy-d-chloro-chromon-7-yloxy)-2hydroxy-propane. 35-40 Disodium salt of l,3-bis( 2-carboxychromon-5-yloxy)-acetone. 30-35 Disodium salt of l,3-bis(2-carboxychromon-5-yloxy)-2-ethoxypropane. 30-35 Clinical investigatins of l,3-bis(2-carboxychromon-5 -yloxy)-2 -hydroxypropane in the form of its disodiumsalt, hereinafter referred to as compound A, have been carried out onvolunteers having clinical evidence of allergic asthma. In the case ofsome of the volunteers this asthma was identified as extrinsic asthma,i.e., was produced by a specific antigen; the majority of thevolunteers, however, were classified as suffering from intrinsic asthma,i.e., did not respond to a large number of skin and aerosol provocationtests.

In the case of the volunteers suffering from extrinsic asthma it waspossible to assess the degree of protection afforded quantitativelyusing the test procedure described above.

In the case of subjects suffering from intrinsic asthma the therapeuticeffect of compound A could be assessed subjectively and by objectivetests of lung function.

The results of the clinical investigation may be summarized as follows:

1 Inhalation of compound A in doses of 1-20 mg. re-

peated at 4 to 8 hour intervals is well tolerated; no side eflects orother evidence of toxicity being observed during a continuous trialperiod of 5 months.

2. The therapeutic effect of compound A may be apparent in 4 hours butincreases for several days with continued therapy, reaching a maximum inl to 2 weeks. A dose of 2-6 mg. 4 to 6 hourly induces a significantimprovement as shown by objective tests of lung function in mild cases.

In more severe cases, doses of up to 20 mg. at 4 to 6 hourly intervalsare required to produce a significant improvement.

In quantitative objective tests it has been found that compound A,administered in a close of 20 mg. gives up to 84 percent protection 2hours after administration, up to percent protection 4 hours afteradministration, and noticeable protection, e.g. about 20 percentprotection 18 hours after administration.

Subjective improvement usually includes:

a. Reduction of chest tightness;

b. Increased tolerance to exercise; and

c. Reduced sputum volume and cough.

Withdrawal of therapy with compound A was followed by a relapse within48 hours in severe cases or after h 7-14 days in mild cases.

The acute i.v. toxicity of compound A, in rate, as been found to be low;i.e. the LB is at least 1,000 mg/Kg.

What is claimed is:

1. A pharmaceutical composition which comprises a pharmaceutical carrierand l,3-bis( 2-carboxychromon5-yloxy)2-hydroxypropane or atherapeutically acceptable ammonium, alkali metal, alkaline earth metalor amine salt thereof, said bis-chromonyl compound being present in anamount of from about 0.5 to about 67 percent by weight of thecomposition.

2. A composition according to claim 1 wherein the bis-chromonyl compoundis in the form of a salt.

3. A composition according to claim 1 in a form suitable foradministration by inhalation.

4. A pharmaceutical composition according to claim 1 comprising asolution or suspension of the active ingredient in water.

5. A pharmaceutical composition according to claim 1 in the form of anaerosol formulation.

6. A pharmaceutical composition according to claim l,-comprising thesolid active ingredient diluted with a solid diluent.

7. A pharmaceutical composition in dosage unit form which comprises apharmaceutical carrier and from one to 50 milligrams ofl,3-bis(2-carboxy-chromon-5- yloxy)-2-hydroxypropane or atherapeutically acceptable ammonium, alkali metal, alkaline earth metalor amine salt thereof.

8. A method for inhibiting the effects of the antigenantibody reactionwhich comprises administering to the patient, per dose, 1 to 50milligrams of l,3-bis(2-carboxy-chromon-S-yloxy)-2-hydroxypropane or atherapeutically acceptable ammonium, alkali metal, alkaline earth metalor amine salt thereof.

9. A method for the prophylactic treatment of asthma which comprisesadministering to the patient, per dose, 1 to 50 milligrams of l,3-bis(2-carb0xychromon-S-yloxy)-2-hydroxypropane or a therapeuticallyacceptable ammonium, alkali metal, alkaline earth metal or amine saltthereof.

10. A method according to claim 9 wherein the bischromonyl compound isemployed in the form of a salt.

2. A composition according to claim 1 wherein the bis-chromonyl compoundis in the form of a salt.
 3. A composition according to claim 1 in aform suitable for administration by inhalation.
 4. A pharmaceuticalcomposition according to claim 1 comprising a solution or suspension ofthe active ingredient in water.
 5. A pharmaceutical compositionaccording to claim 1 in the form of an aerosol formulation.
 6. Apharmaceutical composition according to claim 1, comprising the solidactive ingredient diluted with a solid diluent.
 7. A pharmaceuticalcomposition in dosage unit form which comprises a pharmaceutical carrierand from one to 50 milligrams of1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane or a therapeuticallyacceptable ammonium, alkali metal, alkaline earth metal or amine saltthereof.
 8. A method for inhibiting the effects of the antigen-antibodyreaction which comprises administering to the patient, per dose, 1 to 50milligrams of 1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane or atherapeutically acceptable ammonium, alkali metal, alkaline earth metalor amine salt thereof.
 9. A method for the prophylactic treatment ofasthma which comprises administering to the patient, per dose, 1 to 50milligrams of 1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane or atherapeutically acceptable ammonium, alkali metal, alkaline earth metalor amine salt thereof.
 10. A method according to claim 9 wherein thebis-chromonyl compound is employed in the form of a salt.